Pulmonology

Pulmonary arterial hypertension in the emergency department: A focus on medication management

a b s t r a c t

Pulmonary Arterial hypertension (PAH) is a chronic progressive incurable condition associated with a high de- gree of morbidity and mortality. With over five drug classes FDA approved in the last decade, the significant ad- vancements in the pharmacologic management of PAH has improved long-term outcomes. Drug therapies have been developed to directly target the underlying pathogenesis of PAH including phosphodiesterase type-5 inhib- itors (PDE-5i), endothelin-receptor antagonists (ERAs), guanylyl-cyclase inhibitors, prostacyclin analogues, and prostacyclin receptor agonists. Although these agents offer remarkable benefits, there are significant challenges with their use such as complexities in medication dosing, administration, and adverse effects. Given these conse- quences, PAH medications are classified as high-risk, and the transitions of care process to and from the hospital setting are a vulnerable area for Medication errors in this population. Thus, it is crucial for the emergency depart- ment provider to appropriately identify, manage, and triage these patients through close collaboration with a Multidisciplinary team to ensure safe and effective medication management for PAH patients in the acute care setting.

Published by Elsevier Inc.

  1. Introduction

Pulmonary arterial hypertension (PAH) is a complex pulmonary vas- cular disease characterized by elevated Pulmonary arterial pressures greater than 25 mmHg and increased Pulmonary vascular resistance [1]. Once considered a rare disease, the incidence of PAH has risen over the past decade with more than 3500 patients diagnosed in the United States (U.S.) in 2012 [2]. Although medical advancements in the treatment of PAH have been demonstrated to improve patient out- comes, the mortality remains high at 21.2% in those with advanced ill- ness [3]. Owing to its progressive nature, exacerbations requiring hospitalization for PAH are frequent and account for 12.8 visits out of 100,000 patients seen in the emergency department (ED) each year [1]. Hospitalizations occur secondary to a myriad of disease or drug- related complications such as acute pulmonary crisis, right ventricular failure, and medication toxicity or withdrawal [1].

Treatment decisions for patients with PAH are based on the patients’ World Health Organization (WHO) group and functional class (FC). PAH

* Corresponding author.

E-mail address: [email protected] (A. Barlow).

is classified into five groups based on Pathologic findings, clinical man- ifestations, and etiology. Group 1 is classic PAH, group 2 is pulmonary hypertension (PH) due to left heart disease, group 3 is PH due to hyp- oxia or underlying lung disease, group 4 is chronic thromboembolic PH, and group 5 is (Table 1) multifactorial [4]. The WHO FC categorizes patients based on Symptom burden and is one of the main tools used for treatment decisions [4]. (Table 2).

Historically, there were limited treatment options to improve the prognosis of PAH due to the poor understanding of the pathobiology of the disease. Recent scientific discoveries have unraveled molecular pathways underlying the pathogenesis of PAH and offered a new thera- peutic landscape with targeted therapies that improve long-term sur- vival by approximately 43% [5]. Five Medication classes have been approved by the U.S. Food and Drug Administration for the management of PAH including phosphodiesterase type-5 inhibitors (PDE-5i), endothelin-receptor antagonists (ERAs), guanylyl-cyclase in- hibitors, prostacyclin analogues, and prostacyclin receptor agonists. Each class widely differs in their clinical application given distinct differ- ences in administration, dosing, and toxicity profile. All PAH medica- tions are considered high-risk owing to their narrow therapeutic index, complex administration, and potential for life-threatening

https://doi.org/10.1016/j.ajem.2021.03.072 0735-6757/Published by Elsevier Inc.

Table 1

Classification of pulmonary hypertension.

Group Classification Causes

Prostacyclins also possess off-targeted antiplatelet effects through antagonism of thromboxane A-2 [6]. Deficiencies in prostacyclin pro- duction in PAH lead to increased pulmonary pressures which supports the rationale for exogenous prostanoid administration [7]. The discov-

Group 1

Group 2

Group 3

Group 4

Group 5

Pulmonary arterial hypertension

Pulmonary hypertension due to left-heart disease

Pulmonary hypertension due to lung disease or hypoxia

Chronic thrombotic pulmonary hypertension (CTEPH) Multifactorial pulmonary hypertension

  • Idiopathic pulmonary hypertension
  • Heritable pulmonary hypertension
  • congenital heart disease
  • Drug/toxin induced (ex. amphetamines, SSRIs, dasatinib, cocaine)
  • HIV-associated
  • systemic sclerosis/connective tissue disease
  • Persistent pulmonary hypertension of the newborn
  • Systolic left-sided heart failure
  • Diastolic left-sided heart failure
  • Valvular heart disease
  • Chronic obstructive pulmonary dis- ease (COPD)
  • Interstitial lung disease
  • Obstructive Sleep apnea
  • Alveolar hypoventilation syndrome
  • Chronic and/or recurrent Pulmonary embolisms
  • Metabolic disorders (ex. Gaucher disease, thyroid disorders)
  • Systemic autoimmune conditions (ex. sarcoidosis)
  • Hematologic disorders (ex. Sickle cell anemia, hemolytic anemia)

ery of prostacyclin analogues has improved the prognosis for patients with advanced PAH, WHO Group III-IV, with epoprostenol demonstrat- ing reductions in mortality of 68-70% [8]. Prostacyclin analogues com- mercially available in the U.S. include epoprostenol (continuous intravenous (IV) infusion), treprostinil (continuous subcutaneous, con- tinuous IV infusion, intermittent inhaled, and oral) and iloprost (in- haled). Their distinct route of administration and pharmacokinetics translate into different Clinical responses with varying tolerability pro- file. There are several important considerations regarding dosing, for- mulations, and administration pumps to avoid abrupt withdrawal or inadvertent overdose. A survey from PAH centers in the U.S. regarding errors for prostacyclin infusion policies reported that 68% of in- hospital prostacyclin errors were considered serious, with 29% resulting in a severe adverse event. Nine of these serious errors were believed to have contributed to patient death [9]. Critical safety issues exist with the use of prostacyclins, and ED providers are well positioned to identify the potential for errors and implement the appropriate safeguards to facili- tate their use.

3. Parenteral prostacyclins

Parenteral prostacyclin analogues, epoprostenol (Veletri(R) or Flolan(R)) and treprostinil (Remodulin(R)), are the preferred therapies

Reference: Simonneau G, Gatzoulis MA, Adatia I, et al. updated clinical classification of pul- monary hypertension. Journal of the American College of Cardiology. 2013;62(25):D34- D41.

Table 2

WHO Function Class for pulmonary hypertension.

for use in the inpatient setting. Intravenous administration is advanta- geous to allow for consistent therapeutic prostanoid exposure and ease of titration during an acute dynamic state of critical illness. A 2019 Cochrane review demonstrated reduced morality from intrave- nous prostacyclins (odds ratio (OR) 0.29, 95% confidence interval) CI 0.12-0.69) compared to placebo that was not transferrable to oral or in- haled based therapies [10]. Epoprostenol was the first-FDA approved

WHO

Class

Description

prostacyclin with an ultra-rapid half-life of ~6 min [11]. This short

half-life serves as a double-edged sword, as although epoprostenol

Class I PH without limitation of physical activity and symptoms (dyspnea, fatigue, chest pain)

can be rapidly titrated to attain the desired Therapeutic effect, abrupt discontinuation can result in rapid subtherapeutic concentrations and

Class

II

Class III

Class IV

PH with slight limitation in physical activity but comfortable at rest.

Ordinary physical activity causes undue symptoms

PH with marked limitation in physical activity but comfortable at rest. Less than ordinary physical activity causes undue symptoms.

PH with inability to carry out normal physical activities without symptoms. Symptoms of right-sided heart failure with symptoms at rest sometimes present.

reversal of pulmonary vasodilation within minutes [11]. Further com- plicating its use, epoprostenol is commercially available as two intrave- nous preparations, Veletri(R) or Flolan(R). Flolan(R) is the formulation of epoprostenol with administration complexities due to its short stability of 8 h at Room temperature [12]. To attain a 24-h expiration, the product must remain stored on ice packs that require routine exchanges to pre-

Reference: The task force for the diagnosis and treatment of pulmonary hypertension of

the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) en- dorsed by the International Society of Heart and lung transplantation (ISHLT), Galie N, Hoeper MM, et al. guidelines for the diagnosis and treatment of pulmonary hypertension. European respiratory journal. 2009;34(6):1219-1263.

adverse effects. These medications are highly predisposed to potentially fatal medication errors that can be detrimental to patient outcomes if improperly used. The need for urgent decision making with such high- risk medications in the emergency department (ED) highlights the im- portance for ED providers to have a foundational understanding of these medications and the key considerations for their use in the acute care setting. A multidisciplinary team approach is vital, and in these situa- tions, clinicians should be encouraged to collaborate with nursing, phar- macists, Respiratory therapists, and PAH specialists to facilitate comprehensive collaborative care.

  1. Prostacyclin analogues

Prostacyclins are constitutively expressed within the pulmonary vasculature that mediate smooth Muscle relaxation and vasodilation.

vent temperature fluctuations or can be stored refrigerated at 2 ?C to 8

?C (36 ?F to 46 ?F) [11,12]. The cumbersome design of this formulation bears the consequences of increased workload on nurses to vigilantly monitor temperature changes, ensure timely ice bath exchanges, and document infusion rates to ensure timely delivery of new infusion bags. Given the impractical routine use of Flolan(R), an alternative more chemically stable formulation, Veletri(R) was developed to circumvent these challenges. This formation is free of drug preservation concerns or complicated storage requirements and is stable for up to 24 h at room temperature and for up to 8 days when refrigerated [11]. Mini- mizing the complexities inherent to Flolan(R) makes Veletri(R) a more at- tractive option for use in the fast-paced atmosphere in the ED when vigilant nursing monitoring may not be feasible [6].

Treprostinil offers several practical advantages compared to epoprostenol. Its extended half-life of ~4 h reduces the risk of abrupt withdrawal syndromes if accidental treatment interruptions occur [13]. However, the prolonged half-life can lead to a delayed onset of pharmacologic effect, making its de-novo initiation less favorable in an acute PAH exacerbation. Treprostinil has improved stability at room temperature which negates any labor-intensive administration in the ED. [13] However, treprostinil is formulated in a neutral pH which sup- ports bacterial growth and increases the risk of bacteremia [14]. The

estimated incidence of bacteremia in patients receiving epoprostenol is

0.118 episodes per 1000 treatment-days and 0.938 episodes per 1000 treatment-days in patients receiving treprostinil (hazard ratio (HR) 4.09, 95% CI 1.24-14.53) [15]. Continuous subcutaneous treprostinil was developed to mitigate the risk of infectious complications and com- plex administration requirements associated with central catheter placement [13]. With the subcutaneous formulation, a small catheter is placed under the skin to facilitate continuous delivery which is far less invasive [13]. However, this may be problematic in critically ill pa- tients with septic shock or on high-dose vasopressors where subcutane- ous absorption is impaired and absorption of treprostinil may be unreliable. In this setting, transition to intravenous infusion can ensure therapeutic concentrations are reached. For treprostinil, the conversion from subcutaneous to intravenous is a 1:1, and dose changes are unnec- essary unless a patient is symptomatic. There is no set guidance for switching from parenteral treprostinil formulations to epoprostenol, but given the differences in half-lives between each agent it has been proposed to use a staggering taper with epoprostenol titration with a 10-20% lower target epoprostenol dose compared to the starting treprostinil dose [16]. Consultation with a PAH specialist is recom- mended to ensure safe transition between products and formulations.

The most critical safety measure for prostacyclins is ensuring their

continued use upon ED arrival. Abrupt discontinuation can lead to a rapid pulmonary Hypertensive crisis that can progress to detrimental cardiorespiratory failure and sudden death [17]. This is especially im- portant for epoprostenol given its extremely short half-life where with- drawal symptoms can be observed within minutes. In the setting where a treprostinil infusion is interrupted, there is a longer time period until decompensation is seen, though the same level of caution still applies. Preventative measures to minimize subtherapeutic prostacyclin expo- sure should be prioritized upon patient arrival. For example, centers should adopt a strategy for alternative site of prostacyclin infusion, such as placement of a peripheral access site, to avoid any lapses in treatment in the setting of inadvertent line obstruction, medication leak, and cartridge malfunctions [17,18]. Clinicians should confirm ap- propriate placement of the central catheter and ensure line patency. Nursing staff should be encouraged to clearly label the prostacyclin infu- sion line and ensure no additional medications are concurrently infused to avoid inadvertent boluses or incompatibility issues. If patients arrive with their ambulatory infusion pump, safeguards should be in place to alert clinicians of any potential malfunctions with the delivery device. If the alarm is triggered because the patient is at the end of their dosing interval, patients receiving epoprostenol are encouraged to carry a backup medication cassette at all times. During procedures or transpor- tation, it can be difficult to minimize unintentional medication cessation since some home infusion pumps are incompatible with magnetic reso- nance imaging (MRI) scanners [17]. In this case, extra tubing can be used in order to place the pump outside of the MRI room or replacement with a compatible pump can be performed under consult with a PAH specialist and pharmacist [17,19]. If clinical assessment suggests the pa- tient is experiencing adverse effects from a prostacyclin, the dose may be decreased although under no circumstances should the infusion be turned off or interrupted without consultation with a PAH specialist.

Another area where medication errors occur is prostacyclin dosing. Prostacyclin doses are based on the patient’s actual body weight at the time therapy is initiated, which is termed their “dosing weight”. Doses are gradually titrated on a nanogram per kilogram increment until symptom improvement is attained while minimizing adverse effects [20]. If the dosing weight is updated and adjusted to reflect the patients current weight, patients can have exaggerated changes in response and either experience withdrawal or toxicity. Inappropriate dose adjust- ments can be avoided by confirming established “dosing weight” with the patient’s prescriber or specialty pharmacy to calculate the baseline infusion rate. Ultimately, hospitals should have order-sets and guide- lines to facilitate seamless initiation or continuation of parenteral pros- tacyclins in the inpatient setting [20].

  1. Inhaled prostacyclin analogues

By virtue of their localized route of administration, inhaled prostacy- clins iloprost and treprostinil provide the distinct advantage of targeted drug delivery to the pulmonary vasculature while minimizing systemic adverse effects [20]. Iloprost (Ventavis(R)) is a chemically stable, rapid- acting prostacyclin analogue with a short half-life of 20-30 min [21]. The Pulmonary vasodilatory effects wane quickly, within 90 min, after the dosing interval which requires frequent dosing at 2-h intervals while awake [21]. Rebound pulmonary hypertension is not expected to occur overnight, and patients are not required to be woken from sleep for continued administration [22]. Each treatment can consume up to 15 to 20 min for self-preparation and proper inhalation. This is often not feasible in acute settings and is a substantial time commitment for patients and nurses. The inhaled treprostinil formulation (Tyvaso(R)) is only dosed four times daily, making its administration significantly less time intensive and more suitable for the ED setting [23].

Continued use of inhaled therapies may be problematic in the ED be- cause active patient participation is needed to operate the inhalation de- vices. This may not be feasible if patients present with cognitive impairment or limited airway access [18].) Although patients with PAH are considered critical airways, in acute respiratory decompensa- tion of PAH mechanical ventilation may be required. Limited evidence is available regarding administration of inhaled prostacyclins with me- chanical ventilation given the specialized inhalation devices used to de- liver these medications (I-neb(R) Adaptive Aerosol Delivery(R) or Prodose(R) Adaptive Aerosol Delivery(R) for iloprost, Tyvaso inhalation system(R) for treprostinil) [17,18,22]. Treprostinil is manufactured as an ultrasonic nebulizer that provides automatic timed actuations of the nebulized medication. The nebulizer is not intended for use during mechanical ventilation, and there are no recommendations for config- uring the device into the circuit nor literature to guide effective drug de- livery. There are some studies describing treprostinil delivery through a jet nebulizer and vibrating mesh nebulizer, but these studies were in- vitro and in pediatrics lending limited applicability to the adult popula- tion [24]. Clinicians can consider off-label administration of epoprostenol (Flolan(R) formulation) via continuous nebulization [17]. There is literature to support this conversion when administered with mechanical ventilation and high-flow nasal cannula with aerosolized precautions [17,18]. Drug bioavailability can be problematic in these scenarios, as it has been shown that less than 20% of the drug actually reaches the site of action through this administration technique [17]. The challenge to this route of delivery is the viscous glycine buffer in the Flolan(R) diluent, which can clog the ventilator, resulting in ventilator dysfunction and interruptions in medication delivery. Given the techni- cal challenges with aerosolized administration of epoprostenol, staff should be extensively trained on the nuances associated with this for- mulation to ensure safe use in the ED setting.

  1. Oral prostacyclin analogues

Oral treprostinil (Orenitram(R)) is an oral extended-release tablet de- signed to minimize administration burden and medication errors asso- ciated with IV and inhalED treatments.(PI) Oral treprostinil has a convenient dosing schedule of two to three times daily.(PI) However, there can be challenges to its use. Given this product is an extended- release formulation, it cannot be chewed or crushed for administration via tube feedings. Furthermore, each dose must be timed with a meal that contains at minimum 250 cal and 30-50% fat to ensure adequate bioavailability [22,25]. The medications should be taken as scheduled, because if two or more doses are missed, re-titration from the lowest starting dose is required. Although its application to the treatment algo- rithm in PAH remains to be elucidated, emerging evidence suggests it may serve as a simplified transition therapy from parenteral prostacy- clin analogues in low-risk, Hemodynamically stable patients [26]. De- spite the ease of oral administration, adverse effects (i.e. headaches,

flushing, hypotension) occurs in up to 94-100% of patients on oral treprostinil that can be severe enough to warrant discontinuation in up to 14% of cases [26]. In the ED setting, providers may need to switch to an alternate formulation in the presence of adverse effects, lack of en- teral access, or inadequate home supply. Dose conversions between oral and IV formulations are available, but caution is advised given the high risk of medication errors, and consultation with a PAH specialist is still advised.

  1. Prostacyclin analogue adverse effects

Prostacyclin analogues carry a significant Adverse effect profile that can be difficult to not only manage, but to also accurately discern from symptoms of Disease progression. ED providers should be proactive in their approach to identifying and managing the toxicities of prostacyclin analogues. A majority of the adverse effects are predictable, dose- dependent, and transient during up titration. Owing to their vasodilatory properties, prostacyclin analogues are associated with a risk of hypoten- sion, flushing, peripheral edema, and headache [7]. Rapid uptitration at the initiation of therapy carries the highest risk of hypotension and must be balanced by controlling PAH symptoms. Hypotension can be pro- found in patients with PAH since right ventricular failure is often also present [17,18]. Providers should consider withholding antihypertensives that can exacerbate hypotension during treatment initiation and closely monitor blood pressure throughout therapy. An off-target of prostacyclins is their antiplatelet properties that can result in thrombocytopenia and in- creased incidence of bleeding [20]. Patient with chronic thromboembolic PAH may also be prescribed anticoagulation for management of PAH which further compounds the risk of bleeding. The benefits of anticoagulation in PAH is an area of clinical controversy, with mixed evi- dence of benefit in idiopathic pulmonary hypertension but a clear risk of harm in PAH secondary to scleroderma [4]. The most recent guideline up- date provides no recommendation on anticoagulation given the uncer- tainty of the evidence at this time [4]. Therefore, in the absence of comorbid compelling indications such as pulmonary embolism, the risks of continued anticoagulation therapy exceed the uncertainty of any po- tential benefit and should likely be discontinued. Additional preventative measures to minimize the risk of bleeding include limiting excessive Blood draws [17].

A characteristic adverse effect of prostacyclins is the sensation of lo-

calized jaw pain after the first bite of a meal. Systemic pain syndromes such as myalgias or muscle cramps are also common [27]. Pain can be managed with standard analgesics, but NSAIDs should be avoided as they not only inhibit prostaglandin synthesis but also can potentiate their antiplatelet properties [6]. Permanent catheter placement for the administration of IV prostacyclins predisposes patients to severe infec- tious complications. These infections are rather distinctive in their mi- crobiology patterns and are influenced by product formulation. The predominant pathogens in patients on epoprostenol are gram positive skin microflora, Staphylococcus, and Micrococcus sp. IV treprostinil has been associated with the development of gram-negative infections including Pseudomonas sp. and Enterobacter sp., with coagulase- negative Staphylococcus being less prevalent [13,14]. Treprostinil is as- sociated with a 2-fold increased risk of bacteremia compared to epoprostenol because of its formulation with a diluent that has a neutral pH, producing an environment conducive to bacterial overgrowth [14]. If sepsis is a possible cause for hospital admission, ED providers should assess the medication catheter site as a possible source of infection, en- sure sterility throughout ED interventions, and initiate broad-spectrum antibiotics for empiric coverage against the aforementioned pathogens. Current guidelines established by the Infectious Diseases Society of America (IDSA) recommend any patient with bacteremia and an in- dwelling catheter should have the line removed after alternative access is obtained and the infusion is transferred [28]. The transfer process to an alternative site warrants discussion to minimize excess drug expo- sure or lapse in therapy given the need to prime infusion lines with

concern for “dead space” in the catheter. The alternative administration site to infuse the prostacyclin after removal of the infected catheter should be maintained until clinical defervesce occurs and blood cultures remain negative for 2-4 days. Once clinical stability is achieved and blood cultures are clear, a new tunneled catheter can be placed [29].

Inhaled formulations are associated with the lowest incidence of toxicities. Inhaled Veletri(R) has a greater risk of bronchospasm than Flolan(R) due to its inactive arginine component [17]. While minimizing the risk of bacteremia, the subcutaneous formulation carries a side effect profile of intolerable injection site reactions (85%) leading to poor pa- tient compliance [19]. The most common adverse effects and practical management strategies are outlined in Table 3.

  1. Prostacyclin receptor agonist

Selexipag (Utravi(R)) targets the prostacyclin pathway as a direct ag- onist of the prostacyclin receptor [30]. Selexipag is indicated in WHO Group I, FC II-III, as monotherapy or in combination with an ERA or PDE-5i, to delay disease progression and reduce the risk of hospitaliza- tion [4]. Due to their overlapping pharmacologic properties, selexipag should not be used in combination with prostacyclin analogues as the adverse effects are compounded without additional therapeutic benefit [30]. Selexipag is available as an oral tablet dosed twice daily and re- quires a slow dose titration to limit the risk of hypotension [30]. Admin- istration with food slows the oral absorption without affecting the therapeutic concentration and has been shown to be an effective strat- egy to mitigate the risk of flushing and hypotension. Selexipag carries the same limitations with reconstitution as oral treprostinil as it cannot be split, crushed, or chewed [30]. Selexipag is hepatically metabolized via CYP2C8, and concurrent use with strong inhibitors (ex. gemfibrozil) or inducers (ex. rifampin) should be avoided [30]. Aside from the afore- mentioned adverse effects of prostacyclin analogues, selexipag has been associated with iatrogenic hypo-or hyperthyroidism. The manufacturer requires that routine thyroid function tests be monitored while on ther- apy [30]. Temporary interruptions of selexipag may be expected, given the rarity of the agent on hospital formularies. However, unlike abrupt withdrawal with prostacyclin analogues, temporary interruptions of selexipag have not been shown to lead to acute deterioration up to 14 days following discontinuation [31]. Of note, most of these patients were on background PAH treatments during treatment interruption, and efforts to continue concurrent PAH therapies should be employed. Refer to Table 4 for more details.

PDE-5 inhibitors

Defects in the Nitric oxide signaling pathway is a hallmark fea- ture of PAH. Upregulation of PDE-5 accelerates NO degradation and di- minishes its vasodilatory effects. Directly targeting this mechanism with PDE-5i enables increased NO activity and restoration of pulmonary arte- rial relaxation [6]. Although there are currently four PDE-5i, only two agents are FDA approved for PAH: sildenafil (Revatio(R)) and tadalafil (Adcirca(R)) [32,33]. As monotherapy, these agents improve pulmonary artery pressures and cardiac output in patients with WHO Group I, FC II- III with a low overall burden of disease [4]. Combination therapy with an ERA is synergistic and preferred in this cohort, as specifically tadalafil with ambrisentan has been shown to improve mortality [4].

PDE-5i are generally well-tolerated, orally administered, and far less cumbersome compared to prostacyclin analogues. Pharmacokinetic in- teractions exist with tadalafil and sildenafil since both agents are hepatically metabolized. Co-administration of strong CYP3A4 inhibitors or inducers is contraindicated [32,33]. Dose adjustments are required when co-administered with moderate CYP3A4 inhibitors/inducers (Table 4). Sildenafil has a Short duration of action, approximately 4 h, making it suitable for use during critical illness to allow for flexibility in dose adjustments [32]. It is also available in various formulations (oral tablet, IV, and oral suspension) providing alternative routes of ad- ministration when patients are nil by mouth (NPO), mechanical venti- lated, or when gut integrity is compromised. However, in institutions

Table 3

Prostacyclin analogues.

Brand Name

Iloprost Ventavis(R)

Epoprostenol Flolan(R) Veletri(R)

Treprostinil Remodulin(R)

Tyvaso(R)

Orenitram(R)

Route

Inhaled

IV IV

IV

SQ

Inhaled

Oral

Group and WHO-FC

Group 1 FC III-IV

Group 1 FC III-IV

Group 1 FC III-IV

Group 1 FC III-IV

Group 1 FC II-III

Dose

Administration

2.5 ug 6-9 times daily ? by 5 ug weekly (max.45 ug/day)

I-neb(R) or Prodose(R) Adaptive Aerosol Delivery Systems

2-4 ng/kg/min ?

by 2 ng/kg/min every 15 min as tolerated (max. 25-40 ng/kg/min) Continuous IV infusion via

1.25 ng/kg/min ? by 1.25 ng/kg/min every 4 wks (max. 20 ng/kg/min)

Implantable SQ infusion catheter

18 ug (3 puffs) 4x/day ? weekly by 3 breaths (max. 54 ug/dose)

Tyvaso(R) inhalation delivery system (battery powered)

0.25 mg BID ? by 0.25 mg every 4 days (no maximum dose)

Take with a high fat meal (~200 cal)

Clinical Pearls

Do NOT administered via alternative

tunneled CVC (long-term) or PICC (short-term)

Flolan requires ice

pump infusion pump

SQ preferred over IV to

Not compatible with other

Oral to IV/SQ conversion calculation

nebulizers

If Alternative medication is required, consider switching to nebulized epoprostenol or nitric oxide

packs to maintain stability

Veletri is stable at

room

minimize the risk of blood stream infections Implantable infusion

pump is battery powered

inhalation delivery systems Portable device, must ensure battery is powered

for medication delivery

available if NPO (total daily dose x 139)/(kg)) = IV/SQ (ng/kg/min)

temperature (preferred) Do NOT

discontinue or interrupt the pump under any circumstance

SQ; subcutaenous, IV; intravenous, CVC; central venous cathether, PICC; peripherally inserted central catheter, max.; maximum, NPO; nil per os. References: [1113, 21, 23, 25].

Table 4

Prostacyclin receptor agonist and soluble guanylate cyclase stimulator

Selexipag (Uptravi(R)) Riociguat (Adempas(R))

where alternative product formulations are not available, extemporane- ously compounding the oral tablet by dissolving in 5 mL of sterile water for enteral administration can be used [32]. Sildenafil primarily un-

Group and WHO-FC

Group 1 WHO FC II-III Group 1 and 4 WHO FC II-IV

dergoes non-renal clearance and accumulation is minimal in the setting of acute kidney injury [17].

Dose 200 ug by mouth twice daily -> increase by 200 ug twice daily weekly (max. 1600 ug twice daily)

Adverse Effects Similar to prostacyclin analogues

(hypotension, flushing) Hypothyroidism/hyperthyroidism: monitor TSH, T4 & free T4

1 mg by mouth three times daily -> ? by 0.5 mg three times daily every 2 weeks as tolerated (max. 2.5 mg three times daily)

*Smokers require doses

>2.5 mg three times daily*

Hypotension (? dose if baseline SBP <110 mmHg), transaminitis, GI

symptoms, and flushing (take with meals)

Tadalafil has a different pharmacokinetic profile that may make it less ideal for use in patients who are critically ill in the ED. Tadalafil is only available as an oral tablet that can be compounded into a solution to facilitate delivery via nasogastric tubes [33]. No alternate forms exist which limits continued delivery for patient that are NPO [17]. Renal ex- cretion accounts for ~40% of tadalafil clearance, and exposure is in- creased by 2 to 4-fold with impaired renal function [18]. Accumulation in the setting of critical illness may be compounded by its extended half-life of ~17 h, prolonging the therapeutic effect and risk of hypoten- sion [33]. Withholding a PDE-5i is preferred in the setting of hemody- namic instability due to the low risk of clinical deterioration with

temporary discontinuation. If continuation of PDE-5 inhibitor therapy

Drug

Interactions

Additional Considerations

Avoid with prostacyclin analogues and CYP2C8 Inhibitors (ex. amiodarone)

If doses are missed for >=3 days reinitiate at a lower dose and titrate up slowly

Contraindicated with nitrates and PDE-5 inhibitors

If transitioning to a PDE-5i, wait 24 h to initiate riociguat. If

transitioning to riociguat from a PDE-5i, discontinue sildenafil

24 h or tadalafil 48 h

PRIOR to initiation Contraindicated in pregnancy (REMS program)

If doses are missed for >=3 days reinitiate at a lower dose and titrate up slowly, hazardous medication; do not crush

is warranted, transition to sildenafil is recommended to minimize the risk of accumulation and drug toxicity.

PDE-5 is ubiquitously expressed in vascular endothelium, and the strong vasodilatory activity in other systems may results in headache, flushing, nasal congestion, and dyspepsia [32,33]. PDE-5i are generally well-tolerated, with hypotension being the primary dose limiting ad- verse effect [29]. Fatal hypotension has been reported when PDE-5i are co-administered with nitrates [32,33]. This is of critical importance to ED providers given nitrates are a cornerstone therapy in patients pre- senting with acute decompensated heart failure, a common comorbid condition [34]. There is a high propensity for this interaction to be overlooked in the PAH population since their use for PAH is less well known. These agents are often referred to by their brand names used for Erectile dysfunction, “Viagra” or “Cialis”, instead of the brand names used for PAH. Further, clinicians may refrain from inquiring

TSH; thyroid stimulating hormone, SBP; systolic blood pressure, GI; gastrointestinal, REMS; Risk Evaluation and mitigation strategies.

Reference: [30, 44].

about PDEi therapies in females, given their routine use in benign pros-

tatic hyperplasia and erectile dysfunction. The potential consequences of overlooking this interaction are arguably more dangerous in the

PAH patient as PDE-5i are administered daily (instead of as needed) and the doses used are on the order for 4-5 times higher than alternative in- dications. With these factors combined, the ramifications of such inter- action could be fatal. In recognition of these dangers, the American Heart Association (AHA) published a position statement to enhance provider awareness of this interaction [35]. All patients with a history of PAH, Males and females, should be screened for PDE-5i use. Clinicians should refer to these medications by using their brand and generic names to avoid confusion. A washout period of 24 h for sildenafil and 36 h for tadalafil prior to nitrate administration is required to mitigate this fatal interaction [32,33]. In emergent situations of chest pain and hypertension that require treatment, the use of a non-nitrate alternative such as an opioid and or a beta blocker or calcium channel blocker can be considered when appropriate [36].

Rare toxicities include visual and auditory disturbances. Visual dis- turbances are usually mild and transient, manifesting as increased per- ception to light and Blurred vision [32,33]. In a minority of cases, there is a potential risk for progression to a more Severe form of retinal toxicity known as non-arteritis anterior ischemic optic neuropathy (NAION), a form of irreversible Vision loss. Sildenafil is uniquely associated with transient episodes of blue vision due to off-target inhibition of PDE-6 concentrated in the cone cells of the retina [6,32,33]. Temporary hearing loss may also occur accompanied by tinnitus and dizziness. Cumula- tively, these sensory disturbances are rare, yet distinguished toxicities of PDE-5i that are reversible upon medication discontinuation. Refer to Table 5 for more details.

  1. Endothelin receptor antagonists

Endothelian-1 is an endogenous potent vasoconstrictor that also mediates endothelial proliferation and remodeling. ERA serve as an im- portant therapeutic target for PAH to reverse pulmonary vascular con- striction and improve pulmonary vascular resistance mediated by these pathways [6]. The current ERAs, bosentan, macitentan, and ambrisentan, each elicit their own specificity to ETA and ETB [37-39]. Bosentan and macitentan are dual ETA/ETB receptor antagonists whereas ambrisentan has 4000-fold increased selectivity for the ETA re- ceptors vs ETB [37]. The main therapeutic use for ERAs is in combination with PDE-5i for WHO Group I, FC II-III to improve exercise capacity, he- modynamics, and right ventricular function [4]. These agents require weeks of continued administration until noticeable symptomatic re- sponse is achieved and are indicated for acute symptom control in a PAH emergency.

Bosentan was the first ERA approved for PAH, though it is rarely used in Contemporary practice owing to its toxicities and drug-interactions. Bosentan undergoes extensive hepatic metabolism and should be avoided in patients with mild to moderate hepatic impairment [17]. Drug interactions can pose significant challenges since bosentan is a po- tent inducer of two major CYP isoenzymes CYP2C9 and CYP3A4 [37].

These enzymes are involved in the metabolism of many therapeutic agents used in the ED setting, such as sedatives (ex. midazolam, fenta- nyl), antibiotics (macrolides, fluoroquinolones), or anticoagulants (ex. warfarin), necessitating more aggressive dosing strategies to achieve the same therapeutic response. Ambrisentan and macitentan are hepatically metabolized to a lesser extent and have fewer drug-drug in- teractions [38,39].

ERAs have significant teratogenic potential and are rated pregnancy category X due to the risk of embryo-fetal toxicity including fetal malformations and stillbirths [37-39]. The FDA mandated all ERAs be placed under a risk evaluation and mitigation strategy (REMS) program which requires that women remain on two forms of contraception and receive confirmatory negative pregnancy tests on a monthly basis throughout treatment. Bosentan, in particular, is problematic in this set- ting because it decreases the concentrations of estrogen and progestin in oral contraceptives, placing women at risk for contraceptive failure [37]. Intrauterine devices or implants are the preferred alternatives with bosentan. An additional consideration with the concurrent use of contraception is the prothrombotic potential of hormonal therapy adding to the heightened baseline thromboembolic risk of patients with PAH [40].Female health care providers should also take precau- tions while handling these medications. Nurses should be educated to wear gloves and avoid crushing ERAs tablets since they are included in the NIOSH hazardous medication list [41].

Another REMS element specific to bosentan is the risk for fatal hep- atotoxicity [37]. Dose dependent, reversible hepatotoxicity occurs in up to 10% of patients on any ERA. The incidence is greatest with bosentan due to its inhibition of canalicular bile salt transport [42]. The REMS pro- gram mandates monitoring routine liver function tests during treat- ment. Mild, transient LFT elevations can occur, but often dissipate with dose reduction or switching to a different ERA once LFTs return to base- line. In the presence of shock liver or acute hepatic decompensation, ERAs should be permanently discontinued [17,29,37].

Reductions in hemoglobin by 1 to 1.5 g/dL is expected within the first two weeks of treatment with an ERA and is rarely life-threatening [6]. This complication may be clinically relevant in PAH patients receiv- ing adjunctive warfarin or prostacyclins, predisposing these patients to higher bleeding risk. Inhibition of ETA receptors modulates salt and water retention which can lead to weight gain and Lower extremity edema. Exacerbations of Acutely decompensated heart failure severe enough to warrant hospitalization have been reported within the first 4 to 8 weeks of ERA initiation [37-39]. Ambrisentan carries the highest risk. In patients with PAH complicated by right ventricular failure, this can be a potentially fatal sequela. ED providers should consider with- holding ERA in the setting of volume overload, and initiation of diuresis may be required. Macitentan has minimal impact on fluid retention and may be an ideal alternative when this complicates treatment [43]. Abrupt discontinuation of ERAs has not been correlated with symptoms of withdrawal and should be considered if severe adverse effects of

Table 5

Phosphodiesterase inhibitors.

Sildenafil (Revatio(R)) Tadalafil (Adcirca(R))

Group and WHO-FC Group 1 WHO FC II-IV Group 1 WHO FC II-IV

Dose 20 mg by mouth three times daily (max. 80 mg three times daily) Initial: 20 mg by mouth daily (max. 40 mg daily) Formulation Oral tablets and solution Intravenous Oral tablets Can compound into an oral solution drug interactions Contraindicated with nitrites and ricociguat

24 (sildenafil) or 48 h (tadalafil) of nitrates or riociguat

Alpha blockers, alcohol, anti-hypertensives exacerbate hypotension CYP3A4 inducers/inhibitors

Adverse Effects Common: headache, flushing, hypotension, dyspepsia, myalgias (tadalafil)

Rare: visual color changes (blue/green), vision loss: non-arteritic ischemic optic neuropathy, Retinal hemorrhages, epistaxis Additional Considerations Low risk of severe rebound pulmonary hypertension

Consider discontinuation for symptomatic hypotension or hemodynamic instability, vision or hearing changes, indication for nitrates

References: [32, 33].

Table 6

Endothelin receptor antagonists

Bosentan (Tracleer(R)) Macitentan (Opsumit(R)) Ambrisentan (Letairis(R))

Group and WHO-FC Group 1 WHO FC II-IV Group 1 WHO FC II-IV Group 1 WHO FC II-IV

Dose 62.5 mg by mouth twice daily -> ? to 125 mg by mouth twice daily in 4 weeks

10 mg by mouth daily 5 mg by mouth daily ->

? to 10 mg by mouth daily in 4 weeks

Temporary Discontinuation

Consider for elevated liver function tests (>=3x ULN, see bosentan below*), symptomatic anemia, marked drop in hemoglobin, pregnancy, fluid overload

No withdrawal syndrome if held or discontinued

Drug Interactions Avoid CYP3A4/CYP2C9 substrates/inhibitors/inducers Avoid strong CYP3A4

inducers/inhibitors

Cyclosporine ? ambrisentan

Adverse Effects Hepatotoxicity, anemia, peripheral edema, headaches, pulmonary veno-occlusive disease, decreased spermatogenesis, Liver dysfunction/transaminitis (bosentan)

Additional consideration Contraindicated in pregnancy (REMS program), hazardous (do not crush)

No withdrawal syndrome if held or discontinued; consider holding for elevated LFTs (>=3x ULN, see bosentan below*), symptomatic anemia, or symptomatic fluid overload

LFT; liver function tests, ULN; Upper limit of normal. References: [3739].

these agents are in the differential. It is also safe to temporarily withhold from therapy if a patient is clinically stable on their home therapy but has limited oral access. ERAs are on the NIOSH hazardous drug list due to their teratogenic potential and therefore cannot be crushed for en- teral tube administration [41]. Refer to Table 6 for more details.

  1. Riociguat

Riociguat (Adempas(R)) acts as a potent, direct stimulator of soluble gunaylyl cyclase to potentiate vasodilation through production of free NO. Riociguat is the only agent that has been approved for Chronic Thromboembolic Pulmonary Hypertension (CTEPH) [44]. Given the poor prognosis in this condition, it has been a valuable addition to the therapeutic armamentarium for WHO Group 1 or 4 pH to improve exer- cise capacity and reduce disease progression [4]. Similar to PDE-5i, there is a fatal risk of hypotension when riociguat is co-administered with other agents that modulate the NO pathway including PDE-5i, nitro- glycerin, and other nitrate derivatives. The same precautions should be set in place as mentioned with PDE-5i regarding this interaction. Continuation of this therapy in the hospital setting is complicated by the exorbitant cost and relatively rare use that limits approval on hospi- tal formularies. Continuation of a patient’s home supply or transition to an alternative vasodilator such as sildenafil or tadalafil should be made under the discretion of a PAH specialist. If a PDE-5 is considered as an al- ternative, a washout period of 24 h is required to minimize the risk of fatal hypotension. Similar to ERAs, riociguat is also listen under a REMS program due to its teratogenic risks and carries the same contra- ceptive and monitoring requirements mentioned with the ERAs. Fur- thermore, it is not recommended to crush riociguat for enteral tube of administration due to the teratogenic potential [41]. Refer to Table 4 for more details.

  1. Conclusion

PAH medications are classified as “high-risk medications” because critical safety issues exist with their narrow therapeutic index, complex dosing, unique devices for administration, and toxicity profile. If inap- propriately managed, these agents can have toxicities or withdrawal phenomenon that can result in fatalities. ED providers must be aware of the critical safety issues specifically surrounding prostacyclin use for patients with PAH. Knowledge of the Pharmacokinetic differences be- tween prostacyclin agents and relative adverse effects can assist in preventing detrimental medication errors with these high-risk thera- pies. ED providers should seek involvement of institutional PAH special- ists early to facilitate safe medication use given the complexity of these treatments. The most vital steps ED providers can take when

approaching a patient on prostacyclins is to ensure two peripheral IVs are in place for patients on continuous infusion in addition to performing a thorough physical exam of the catheter line to ensure pa- tency and prevent abrupt discontinuation of IV prostacyclin analogues. As the likelihood of encountering PAH patients in the ED is increasing, it is important for ED providers to be well-versed on these pharmaco- logic agents and appropriate management in the ED setting.

Declaration of Competing Interest None.

References

  1. Stein PD, Matta F, Hughes PG. Scope of problem of pulmonary arterial hypertension. Am J Med. 2015;128(8):844-51. https://doi.org/10.1016/j.amjmed.2015.03.007.
  2. Mcgoon MD, Miller DP. REVEAL: a contemporary US pulmonary arterial hyperten- sion registry. Eur Respir Rev. 2012;21(123):8-18. https://doi.org/10.1183/ 09059180.00008211.
  3. Hoeper MM, Kramer T, Pan Z, et al. Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratifica- tion model. Eur Respir J. 2017;50(2). https://doi.org/10.1183/13993003.00740- 2017.
  4. Klinger JR, Elliott CG, Levine DJ, et al. Therapy for pulmonary arterial hypertension in adults: update of the CHEST guideline and expert panel report. Chest. 2019;155(3): 565-86. https://doi.org/10.1016/j.chest.2018.11.030.
  5. Galie N, Manes A, Negro L, Palazzini M, Bacchi-reggiani ML, Branzi A. A meta- analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30(4):394-403.
  6. Bishop BM, Mauro VF, Khouri SJ. Practical considerations for the pharmacotherapy of pulmonary arterial hypertension. Pharmacotherapy. 2012;32(9):838-55. https:// doi.org/10.1002/j.1875-9114.2012.01114.x.
  7. Gomberg-maitland M, Olschewski H. Prostacyclin therapies for the treatment of pul- monary arterial hypertension. Eur Respir J. 2008;31(4):891-901. https://doi.org/10. 1183/09031936.00097107.
  8. Galie N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D60-72.
  9. Kingman MS, Tankersley MA, Lombardi S, et al. Prostacyclin administration errors in pulmonary arterial hypertension patients admitted to hospitals in the United States: a national survey. J Heart Lung Transplant. 2010;29:841-6. https://doi.org/10.1016/j. healun.2010.03.008.
  10. Barnes H, Yeoh HL, Fothergill T, Burns A, Humbert M, Williams T. Prostacyclin for pulmonary arterial hypertension. Cochrane Database Syst Rev. 2019;5:CD012785.
  11. Veletri (epoprostenol) [prescribing information]. South San Francisco, CA: Actelion Pharmaceuticals US Inc; July 2017.
  12. Flolan (epoprostenol) [product monograph]. Mississauga, Ontario, Canada: GlaxoSmithKline Inc; February 2019.
  13. Remodulin (treprostinil) [prescribing information]. Research Triangle Park, NC: United Therapeutics Corp; July 2018.
  14. Bloodstream infections among patients treated with intravenous epoprostenol or in- travenous treprostinil for pulmonary arterial hypertension-seven sites, United States, 2003-2006. MMWR Morb Mortal Wkly Rep. 2007;56(8):170-2.
  15. Lopez-medrano F, Fernandez-ruiz M, Ruiz-cano MJ, et al. High incidence of blood- stream infection due to gram-negative bacilli in patients with pulmonary hyperten- sion receiving intravenous treprostinil. Arch Bronconeumol. 2012;48(12):443-7.
  16. Reisbig KA, Coffman PA, Floreani AA, Bultsma CJ, Olsen KM. Staggered transition to epoprostenol from treprostinil in pulmonary arterial hypertension. Ann Pharmacother. 2005;39(4):739-43. https://doi.org/10.1345/aph.1E418.
  17. Torbic H. Management of Pulmonary Arterial Hypertension in the ICU. J Pharm Pract.

2019;32(3):303-13. https://doi.org/10.1177/0897190019838110.

  1. Muzevich KM, Chohan H, Grinnan DC. Management of pulmonary vasodilator ther- apy in patients with pulmonary arterial hypertension during critical illness. Crit Care. 2014;18:523. https://doi.org/10.1186/s13054-014-0523-z.
  2. Stewart T. Pulmonary arterial hypertension: a focus on infused prostacyclins. J Infus Nurs. 2016;39(5):315-26. https://doi.org/10.1097/NAN.0000000000000190.
  3. Coons JC, Clarke M, Wanek MR, Bauer A, Bream-rouwenhorst HR. Safe and effective use of prostacyclins to treat pulmonary arterial hypertension. Am J Health Syst Pharm. 2013;70(19):1716-23. https://doi.org/10.2146/ajhp130005.
  4. Ventavis (iloprost) [prescribing information]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc; October 2017.
  5. Farber HW, Gin-sing W. Practical considerations for therapies targeting the prosta- cyclin pathway. Eur Respir Rev. 2016;25(142):418-30. https://doi.org/10.1183/ 16000617.0083-2016.
  6. Tyvaso (treprostinil) [prescribing information]. Research Triangle Park, NC: United Therapeutics Corp; October 2017.
  7. Parker DK, Shen S, Zheng J, et al. Inhaled Treprostinil drug delivery during me- chanical ventilation and spontaneous breathing using two different nebulizers. Pediatr Crit Care Med. 2017;18(6):e253-60. https://doi.org/10.1097/PCC. 0000000000001188.
  8. Orenitram (treprostinil) [prescribing information]. Research Triangle Park, NC: United Therapeutics Corp; October 2019.
  9. Coons JC, Miller T. Extended-release oral treprostinil in the management of pulmo- nary arterial hypertension: clinical evidence and experience. Ther Adv Respir Dis. 2018;12. https://doi.org/10.1177/1753466618766490.
  10. Kingman M, Archer-Chicko C, Bartlett M, Beckmann J, Hohsfield R, Lombardi

S. Management of prostacyclin side effects in adult patients with pulmonary arterial hypertension. Pulm Circ. 2017;7(3):598-608. https://doi.org/10.1177/ 2045893217719250.

  1. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the infec- tious diseases society of america. Clin Infect Dis. 2009;49(1):1-45. https://doi.org/ 10.1086/599376.
  2. Bauer SR, Tonelli AR. Beyond the evidence: treating pulmonary hypertension in the intensive care unit. Crit Care. 2014;18:524. https://doi.org/10.1186/s13054-014- 0524-y.
  3. Uptravi (selexipag) [prescribing information]. South San Francisco, CA: Actelion Pharmaceuticals US Inc; September 2019.
  4. Preston IR, Channick RN, Chin K, et al. Temporary treatment interruptions with oral selexipag in pulmonary arterial hypertension: insights from the prostacyclin (PGI) receptor agonist in pulmonary arterial hypertension (GRIPHON) study. J Heart Lung Transplant. 2018;37(3):401-8. https://doi.org/10.1016/j.healun.2017.09.024.
  5. Revatio (sildenafil citrate) [prescribing information]. New York, NY: Pfizer Labs; Jan- uary 2019.
  6. Adcirca (tadalafil) [prescribing information]. Indianapolis, IN: Eli Lilly and Company;

May 2017.

  1. Guazzi M, Naeije R. Pulmonary hypertension in heart failure: pathophysiology, pathobiology, and emerging clinical perspectives. J Am Coll Cardiol. 2017;69(13): 1718-34.
  2. Cheitlin MD, Hutter Jr AM, Brindis RG, et al. Use of sildenafil (Viagra) in patients with cardiovascular disease. Technol Pract Execut Commit Circ. 1999;99(1):168-77.
  3. Rosen RC, Jackson G, Kostis JB. Erectile dysfunction and cardiac disease: recommen- dations of the second Princeton conference. Curr Urol Rep. 2006;7(6):490-6. https://doi.org/10.1007/s11934-006-0060-7.
  4. Tracleer (bosentan) [prescribing information]. South San Francisco, CA: Actelion Pharmaceuticals; April 2019.
  5. Opsumit (macitentan) [product monograph]. Toronto, Ontario, Canada: Janssen Inc; August 2019.
  6. Volibris (ambrisentan) [product monograph]. Mississauga, Ontario, Canada: GlaxoSmithKline Inc; September 2018.
  7. Bazan IS, Fares WH. Hypercoagulability in pulmonary hypertension. Clin Chest Med. 2018;39(3):595-603. https://doi.org/10.1016/j.ccm.2018.04.005.
  8. Connor TH, MacKenzie BA, DeBord DG, et al. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication Number 2016-161; 2016.
  9. Fattinger K, Funk C, Pantze M, et al. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reac- tions. Clin Pharmacol Ther. 2001;69(4):223-31. https://doi.org/10.1067/mcp.2001. 114667.
  10. Khadka A. Singh brashier DB, Tejus a, Sharma AK. Macitentan: an important addition to the treatment of pulmonary arterial hypertension. J Pharmacol Pharmacother. 2015;6(1):53-7.
  11. Adempas (riociguat) [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; January 2018.